The invention provides a composition comprising a carrier phase and at least one additional phase, said at least one additional phase being immiscible with the carrier phase or being partially miscible with the carrier phase, whereby a change in ambient conditions alters the viscosity of the carrier phase.
Drugs can be administered parenterally as a depot formulation for the treatment of certain diseases. Besides classical dosage forms, such as oily suspensions, modern dosage forms on the basis of biocompatible/biodegradable polymers can be used. The implants (single-unit systems) or microparticles (multiparticulate systems) are prepared from the solid polymeric carriers and are then placed in the body by implantation or injection.
For the implant preparation, the drug is mixed with the carrier (e.g., a polymer) and is then processed into the desired implant shape (e.g., cylinder, pellet, film, fiber), for example, by extrusion or compression at elevated temperatures. Such solid implants are then usually placed in the body by a surgical procedure or through hollow needles with a large diameter.
Drug-containing microparticles can be used in order to circumvent such surgical procedures with implants, which are highly undesired by patients. Suspensions of these particles can be injected with a syringe through an injection needle. These microparticles are prepared outside the body by various processes, such as, for example, the solvent evaporation technique, the organic phase separation technique, or a spray-drying technique. In the solvent evaporation method, which is frequently used for the preparation of biodegradable microparticles, a drug is dissolved or dispersed in a solution of a biodegradable polymer (e.g., polylactic acid) in a solvent (e.g. methylene chloride), which is not miscible with water. This drug-containing polymer phase is then emulsified in an external aqueous phase and forms drug-containing polymer droplets. The microparticles are obtained after evaporation of the solvent through the solidification of the polymer and are then separated from the aqueous phase (e.g., by filtration) and dried.
Commercially available biodegradable microparticle products (e.g., Decapeptyl, Enantone) consist of a dry powder of the microparticles and an aqueous suspension vehicle. The microparticles and the aqueous suspension vehicle are stored separately, for example, in two-chamber syringes or in two ampoules, because of the hydrolytic instability of the biodegradable polymers. The microparticles are then suspended in the aqueous suspension vehicle just prior to the administration and are then injected.
The preparation of these biodegradable particle products is very elaborate and has to be done under sterile or aseptic conditions. In addition, most microencapsulation processes are difficult or not at all transferable to the production size and are dependent on many process and formulation variables. The suspension of the microparticles and the subsequent injection can also cause difficulties (e.g., agglomeration, residual microparticles in the syringe, clogging of the needle, etc.).
Besides the water-insoluble polyactic acid derivatives and other water-insoluble polymers, hydrophilic polymers can also be used as carrier materials for microparticles and implants. Microparticles of hydrophilic polymers (e.g., polysaccharides, such as alginates or chitosan, cellulose derivatives, protein-(collagen) derivatives) can be prepared, for example, through spray-drying or w/o-emulsification techniques, whereby the drug-containing aqueous polymer solution is either spray-dried or emulsified into an external oil phase, whereby the particles are obtained after removal of the water, washing, filtration and drying. Like the processes for the preparation of polyactic acid microparticles, the microencapsulation techniques with the hydrophilic polymers are also very elaborate.
A composition based on a drug-containing polymer solution was developed in order to avoid problems with the preparation and administration of implants or microparticles U.S. Pat. No. 4,938,763). Thereby, a solution of polylactic acid (or a derivative) is injected into the body, for example, intramuscularly or subcutaneously, and an implant is formed in-situ through the precipitation of the polymer in the tissue. The implant is therefore not formed outside, but inside the body. The polymer solution has to be injectable through a needle; it therefore cannot be too viscous. The possible polymer content is therefore primarily limited through the viscosity of the polymer solution and not through the solubility of the polymer. In addition, precipitation of the polymer during the injection of the polymer solution can negatively influence the injection of the remaining polymer solution. Disadvantages of this method are also the use of high amounts of solvents with toxicity and compatibility problems and, after injection into soft tissue, the somewhat uncontrollable solidification of the polymer with a not exactly defined surface area of the implant. This can lead to irreproducible release profiles. In addition, the drug can be released rapidly prior to the solidification of the polymer solution. This so-called burst-effect is usually undesirable.
Some systems were developed, whereby a solidification/viscosity increase of drug-containing polymer solutions after administration/injection in the body was caused primarily by a temperature-change or by a pH-change or by special substances (e.g., ions), and not by diffusion of the solvent. These systems have the same disadvantages as the system described in the previous paragraph.